1. Field of the Invention
The inventions disclosed and taught herein relate generally to photokinetic delivery of biologically active substances across a mammalian ocular surface. More particularly, the invention provides methods, apparatus, and compositions for the transcleral/transcorneal, ocular delivery of biologically active substances, such as therapeutic agents, using pulsed incoherent light.
2. Description of the Related Art
Millions of people worldwide suffer from ocular diseases, many of which lead to visual impairment. Anterior segment diseases (dry eye, eye lid diseases) can be successfully treated with topical administration of drugs in eye-drop formulation. However, this minimally invasive technique only allows for less than about 5%, and many times less than 1%, of the administered drug to reach the drug target site before being washed away by tear formation or being absorbed systemically by the surrounding eye tissues. Eye drops may not be an effective method for administering larger molecular weight drugs into the eye for treatment of posterior segment eye diseases such as age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and primary ocular lymphoma.
Systemic administration of an eye targeted drug has very poor bioavailability within the eye due to blood-ocular barriers that normally protect the eye from circulating antigens, inflammatory mediators, and pathogens. Typically, systemic administration does not yield therapeutic drug levels in the posterior vitreous, retina, or choroid, and although systemic administration can deliver drugs to the posterior eye, the large systemic doses necessary to achieve intraocular therapeutic levels are often associated with significant side effects.
As a result of these issues, direct intravitreal drug administration by needle injection is the current standard of care for many diseases of the eye. Recent drug formulation technologies have provided increased bioavailability and sustained release of drugs that are delivered by intravitreal needle injection. Even with drug formulation advancements, repeated invasive injections are required over extended periods of months and years. Intravitreal administration of drugs by needle injection is associated with an entirely new set of potentially catastrophic side effects such as infection, intravitreal hemorrhage or retinal detachment. Estimates in the literature range from 0.02% (Peyman, et al, Retina, Vol. 29(7), pp. 875-912 (2009)) to 0.2% (Jager, R. D., et al., Invest. Ophthalmol. Vis. Sci., 45 (2004)) which would result in between 200 to 2,000 iatrogenic potentially blinding eye infections this year alone. Retinal detachment is estimated at 0.9% prevalence (Jager, 2004) from intravitreal injection, which translates to approximately 9,000 retinal detachments this year from this procedure. Additionally, ocular injections are painful and costly. Many disease states may require frequent drug administration directly into the eye to reach and maintain therapeutic levels. An effective, minimally invasive method of intraocular drug delivery is wanting. The proposed ocular drug delivery system overcomes the problems with repeated ocular needle injections and may be simple enough for home use.
It is widely recognized that stimulation of the optical sites of organic molecules result in conformational changes of the molecule which may produce a physical change in the shape of the molecule. When this stimulation is stopped the molecule would then return to a resting state and original physical shape. Also, if the stimulation is a low power, the relaxational time would be longer than if the molecule was stimulated with high optical power. The combination of low power and slow cyclical stimulation of the molecular optical sites would result in reversible conformational changes causing the molecule to bend and flex resulting in gross physical movement.
Passive transmembrane permeation is generally time and molecular weight (MW) dependent wherein larger molecules have less permeation flux rates than smaller molecules. While not intending to be bound by any theories, it is hypothesized that if a drug molecule in a pharmacologically acceptable formulation is placed on the surface of the sclera/cornea and cyclically illuminated with a selected wavelength of light at a selected pulse rate, the resulting cyclic physical shape change of the molecule may cause gross movement and result in the migration of the molecule across the sclera membrane. It is further hypothesized that narrow wavelength incoherent (non-laser) light from a light emitting diode (LED) source could be used for optical stimulation and that non-ionizing visible light with these characteristics would not be harmful to the drug molecule or the sclera itself. Applicants further hypothesize that the permeation with this system may be less molecular weight dependent than with passive transmembrane permeation methodologies.
The penetration of biologically active substances through the intraocular tissues occurs by either passive or active transport mechanisms, typically through the corneal and/or the non-corneal (conjunctival-scleral) pathways. Passive delivery or diffusion relies on a concentration density gradient between the drug at the outer surface and the inner surface of the biological barrier to be penetrated. The diffusion rate is proportional to the gradient and is modulated by a molecule's size, hydrophobicity, hydrophilicity and other physiochemical properties as well as the area of the absorptive surface. Typically, topically applied drugs reach the intraocular tissues by either the corneal and/or the non-corneal (conjunctiva-scleral) pathways, and efforts have been focused on either enhancing transcellular drug penetration by increasing drug lipophilicty through the use of prodrugs or analogs, or improving paracellular penetratioin by using enhancers to open tight junctions (Lee, et al., J. Ocul. Pharmacol., Vol. 2, pp. 67-108 (1986)). However, it is common to see about 1% or less of an applied dose absorbed across the cornea and conjunctiva to reach the anterior segment of the eye (Lee, et al., in RETINA, 3rd Ed., Mosby, St. Louis, pp. 2270-2285 (2001)). Examples of passive delivery systems include ocularly-applied transdermal patches for controlled delivery of, for example, enkephalins, leupeptin (serine protease inhibitor), camostat mesylate (aminopeptidase inhibitor), nitroglycerine (angina), scopolamine (motion sickness), fentanyl (pain control), nicotine (smoking cessation), estrogen (hormone replacement therapy), testosterone (male hypogonadism), clonidine (hypertension), and lidocaine (topical anesthesia). The controlled delivery of these drugs can include the use of polymer matrices, reservoirs containing drugs with rate-controlling membranes and drug-in-adhesive systems.
In contrast, active delivery relies on ionization of the drug or other pharmacologically active substances and on means for propelling the charged ions through the tissue. The rate of active transport varies with the method used to increase movement and propulsion of ions, but typically this transport provides a faster delivery of biologically active substances than that of passive diffusion. Active transport delivery systems include methods such as subconjunctival ocular drug delivery, iontophoresis (transcleral and transcleral/conjunctival), and a variety of other routes which involve carrier-mediated drug transport systems.
Subconjunctival ocular drug delivery is an active transport method of attempting to elevate intraocular drug concentrations and minimize the frequency of dosing. Compared with direct intravitreal injection, this approach is less risky to the patient, and less invasive. Since the sclera is much more permeable than conjunctiva, the formidable permeability barrier consisting of both the cornea and the conjunctiva can be avoided all together with this approach. Advantages of subconjunctival ocular drug delivery, such as by the use of subconjunctival implants with nano-/microparticles and matrix materials, compared to subconjuctival injection of solution, is the achievement of higher drug concentrations and sustained release of the drug into both the vitreous humor and retinal areas (Gilbert, J. A., et al., J. Control. Release, Vol. 89, pp. 409-417 (2003)).
Iontophoresis is a technique used to guide one or more therapeutic ions in solution into the tissues and blood vessels of the body by means of a galvanic or direct electrical current supplied to wires that are connected to skin-interfacing electrodes. Although ionotophoresis provides a method for controlled drug delivery transdermally, irreversible skin damage can occur from galvanic and pH burns resulting from electrochemical reactions that occur at the electrode and skin interface. Consequently, its application to ocular therapies has been limited, with limited reports of its use in delivering molecules into the eyes of patients. For example, Asahara reported the use of transscleral iontophoresis to deliver 6-carboxyfluorescein-labeled phosphorothioate oligonucleotides and a 4.7 kb plasmid that expressed the green fluorescent protein (GFP) into albino rabbit eyes, with the nucleotides being detected in the anterior chamber, vitreous, and posterior retina with no alteration in length of the oligonucleotides (Asahara, et al., Japn. J. Ophthalmol., Vol. 45, pp. 31-39 (2001)). More recently, a low-current, non-invasive iontophoretic treatment using dexamethasone-loaded hydrogels showed potential value in increasing the drug penetration to the anterior and posterior segments of the eye (see, Eljarrat-Binstock, E., et al., J. Controlled Release, pp. 386-390 (2005); and Myles, M. E., et al., Advanced Drug Delivery Reviews, Vol. 57, pp. 2063-2079 (2005)).
Other approaches to ocular drug delivery problems have included the use of ocular/ophthalmic inserts (e.g., OCUFIT SR®), collagen shields, vesicular systems, the use of liposomes and niosomes, the development of bioadhesives, mucoadhesive dosage forms, the use of lyophilisate carrier systems, and the use of nanoparticles and microparticles such as nanospheres made up of poly-d,l-lactic acid (PLA), polymethylmethacrylate (PMMA), cellulose, poly-ethyl-caprolactone (PECL), or even chitosan (CS) nanoparticles (DeCampos, et al., Pharm. Res., Vol. 21(5), p. 803 (2004)) as part of polymeric drug delivery systems for drug absorption in the eye. These approaches to drug delivery to the eye have been reviewed extensively in the medical literature (see, Das, S. & Suresh, P. K., Int'l. J. Drug Delivery, 2, pp. 12-21 (2010); and, Sultana, Y., et al., Current Drug Delivery, Vol. 3, pp. 207-217 (2006)). However, many of these approaches suffer limitations as well, such as being suitable only for delivering therapeutic molecules of a limited size (e.g., molecular weights of less than 200 Da), or unappealing side affects or potential for added eye damage for the patient seeking treatment.
Because of the inherent problems of the above-identified methods, a need exists for a safe and efficient transocular drug delivery method that eliminates side-effects and damage to the barrier function or appearance of the patient's eye caused by drug administration, and allows for a wide range of biologically active substances to be administered by such a method in therapeutically effective amounts. It would therefore be desirable to provide compositions, methods, and apparatuses to address these problems.
In vitro methods described within the present disclosure were developed to demonstrate the facilitated translocation of two separate compounds through sclera and corneal tissue using pulsed light. These in vitro studies, as described herein, suggest that the hypotheses proposed by the applicants been confirmed. The method of ocular drug delivery by pulsed incoherent light as described herein is referred to as “Photokinetic Ocular Drug Delivery” (PODD).